REVIEW - HLA-B27 in health and disease: a double-edged sword?

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Rheumatology 2002; 41: 857-868

Reviews

HLA B27 in health and disease: a double-edged sword?

The 2000 Mason Prize Essay

P. Bowness

Nuffield Orthopaedic Hospital, Windmill Road, Headington, Oxford OX3 7LD, UK

Abstract

The strong association of the HLA class 1 allele HLA B27 with

ankylosing spondylitis (AS) has been recognized for over 25 yr,

however the pathogenic mechanism linking HLA B27 with AS and other

spondyloarthropathies remains a mystery. We now know that the

principal natural function of HLA B27 is an immunologic one, namely to

bind antigenic peptides and then present them to T lymphocytes. I have

shown that HLA B27 functions as an excellent antigen-presenting

molecule in both spondyloarthropathy patients and healthy individuals.

A working molecular model of how T cells recognize HLA B27 has been

generated and tested. Evidence that T cells have a role in

spondyloarthritis has also been found. First, expanded populations of

T lymphocytes were found in both the blood and synovial fluid of

patients with reactive arthritis (ReA). Secondly, a strong cytotoxic

T-cell response to an HLA B27-restricted peptide epitope from

Chlamydia trachomatis was found in a patient with ReA. This peptide,

derived from a bacterium known to trigger ReA, is thus a candidate

'arthritogenic' peptide. We have also found evidence that HLA B27 has

an unusual cell biology compared with other HLA molecules. HLA B27

demonstrates an unusual ability to form heavy chain homodimers in

vitro. Dimerization is dependent upon disulphide bonding through an

unpaired cysteine at position 67. Remarkably these dimers lack ß2

microglobulin, previously thought to be an essential component of all

mature MHC class 1 molecules. HLA B27 homodimer formation has also

been demonstrated in certain cell lines in vivo, and preliminary data

suggest that significant numbers of T cells from patients with

spondyloarthropathy express a ligand for HLA B27 homodimers. These

findings have extended our understanding of the beneficial immunologic

function of HLA B27, and have also led us to propose the testable new

hypothesis that HLA B27 heavy chain dimerization may be involved in

the pathogenesis of spondyloarthritis.

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Read the full essay here:

http://rheumatology.oxfordjournals.org/cgi/content/full/41/8/857

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